This Program Project will use rodent models to evaluate the effects of exposure to dietary estrogens at various points in the lifespan on disease processes associated with aging. These include breast tumor growth, obesity and cognitive decline, which is the focus of this project. The central premise is that the dose, timing of exposure during the lifespan and target tissue will determine whether the biological effects are beneficial or detrimental. Doses and exposure periods that have beneficial effects in one tissue may have detrimental effects in others. The initial specific aim of this project is to characterize the effects of low and high physiologic doses of estrogen replacement on cognitive function in ovariectomized young, middle-aged and old female rats. These studies will establish a detailed profile of estrogen actions on a broad range of cognitive functions, determine whether the profile of effects differs in young, middle-aged and old rats, and elucidate the effects of low vs. high physiologic levels of estrogen in young middle-aged and old rats. The focus will be on tests of executive functions such as cognitive flexibility, working memory, attention, and response inhibition. The role of estrogens in regulating these aspects of cognition is not well understood, particularly in rodent models. Detailed analysis of response patterns across trials will help to identify the underlying behavioral mechanisms response for estrogen-mediated changes in cognition. The second aim is to test ovariectomized young, middle-aged and old rats exposed to low, medium or high physiologic doses of soy isoflavones on the same battery of tests. Pure soy isoflavones including genistein and equol will be tested first followed by the commercial mixture, Novasoy. These studies will establish a profile of soy effects of soy isoflavones on cognition and identify differences between these compounds and estradiol. An ancillary goal is to measure adipose deposition in the same rats that are tested for cognitive function. Assessing two critical health endpoints in the same animals will allow us to determine how the dose-response and pattern of beneficial vs. harmful effects for the two endpoints are related. The final aim is to use selective estrogen receptor alpha (ERalpha) and beta (ERbeta) antagonists to investigate the role of ERalpha and ERbeta in mediating the actions of soy isoflavones on cognition. Because soy isoflavones show selectivity for ERbeta, we expect them to differentially effect cognitive functions regulated primarily by ERbeta. Together with the other projects in this program these studies will help to define the risk and benefits to older women from consuming dietary estrogens.